2-arm Trial of Paclitaxel Plus Bevacizumab vs. Capecitabine Plus Bevacizumab

Inclusion Criteria

• Written informed consent obtained prior to any study-specific procedure.
• Age ≥18 years.
• Able to comply with the protocol.
• Histologically or cytologically confirmed, HER2-negative, adenocarcinoma of the breast with measurable or non-measurable locally recurrent or metastatic disease, who are candidates for chemotherapy. Locally recurrent disease must not be amenable to radiotherapy or resection with curative intent.
• Eastern Cooperative Oncology Group (ECOG) performance Status (PS) of 0-2.
• Life expectancy more than 12 weeks.
• Prior (neo)adjuvant chemotherapy is allowed provided that the last dose of chemotherapy was more than 6 months prior to randomization. However, if (neo)adjuvant chemotherapy was:
• Taxane-based, patients are eligible only if they received their last taxane more than 12 months prior to randomization.
• Anthracycline-based, the maximum cumulative dose of prior anthracycline therapy must not exceed 360 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin.
• Prior adjuvant radiotherapy is allowed as part of the treatment of early breast cancer provided that last fraction of radiotherapy occurred at least 6 months prior to randomization. Radiotherapy administered solely for the relief of metastatic bone pain is allowed prior to study entry, providing that:
• no more than 30% of marrow-bearing bone was irradiated
• the last fraction of radiotherapy was administered ≥ 3 weeks prior to randomization.
• Adequate left ventricular ejection function (LVEF) at baseline, defined as LVEF ≥ 50% by either echocardiogram or multigated acquisition scan (MUGA).
• Adequate hematological function
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Hemoglobin ≥ 9 g/dL (may be transfused to maintain or exceed this level).
• Adequate liver function
• Total bilirubin ≤ 1.25 x upper normal limit (ULN)
• Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) 2 at randomization.
• Evidence of spinal cord compression or current evidence of central nervous system (CNS) metastases (even if previously treated). If suspected, the patient should be scanned by CT or magnetic resonance imaging (MRI) within 28 days prior to randomization to rule out spinal / CNS metastases.
• History or evidence upon physical/neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of the study treatment.
• Minor surgical procedures, including insertion of an indwelling catheter, within 24 hours prior to randomization.
• Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day).
• Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
• History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg).
• Clinically significant (i.e. active) cardiovascular disease, requiring medication during the study and might interfere with regularity of the study treatment, or not controlled by medication.
• Non-healing wound, active peptic ulcer or bone fracture.
• History of abdominal fistula, or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of randomization.
• Active infection requiring i.v. antibiotics at randomization.
• Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start.
• Women of childbearing potential (< 2 years after the last m